Therapeutic Possibilities in the Autosomal Recessive Limb-Girdle Muscular Dystrophies

Abstract

Summary:Fourteen years ago, the first disease-causing mutation in a form of autosomal recessive limb-girdle muscular dystrophy was reported. Since then the number of genes has been extended to at least 14 and the phenotypic spectrum has been broadened. The generation of mouse models helped to improve our understanding of the pathogenesis of the disease and also served to study therapeutic possibilities. All autosomal recessive limb-girdle muscular dystrophies are rare diseases, which is one reason why there have been so very few controlled clinical trials. Other reasons are insufficient natural history data and the lack of standardized assessment criteria and validated outcome measures. Currently, therapeutic possibilities are mainly restricted to symptomatic treatment and the treatment of disease complications. On the other hand, new efforts in translational research and the development of molecular therapeutic approaches suggest that more promising clinical trials will be carried out in autosomal recessive limb-girdle muscular dystrophy in the next several years.

An Omega-3 Fatty Acid-Enriched Diet Prevents Skeletal Muscle Lesions in a Hamster Model of Dystrophy

“…So far, lipid nutritional therapy using conjugated linolenic acid has been investigated only as complement to corticosteroids intervention in the attempt to attenuate fat gain. 8 Furthermore, this treatment, as well as many other different strategies [3][4]16,43 in vain used, has been administered when fibrosis was irreversibly established and not before its onset, very likely owing to the lack of efficient techniques to anticipate the diagnosis. [5][6]21 Because muscular dystrophy begins early in embryonic development, [41][42][43][44] designing early treatment protocols is reasonable and mandatory to ameliorate the disease 6,45 clinical outcome.…”

“…3 Indeed, owing to the multiplicity of mutated proteins involved, no universal treatment can be envisioned for dystrophic diseases, and an effective therapy is still lacking. In this context, protocols based on different drugs, genes, and cells have been proposed to counteract muscle derangement, [2][3][4] and nutritional supplements have been considered in the attempt to increase muscle strength and prevent myocyte catabolism [5][6][7] or to decrease corticosteroid side effects. 8 3 and 6 polyunsaturated fatty acids (PUFAs) are metabolically and functionally distinct and often have opposing physiological effects.…”

A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping

“…γ-Sarcoglycan is a dystrophin-associated protein, and loss of function mutations in the SGCG gene produces a clinical picture similar to what is seen in Duchenne muscular dystrophy (DMD) (Ben Jelloun-Dellagi et al, 1990;Matsumura et al, 1992). There is currently no effective treatment for this form of LGMD, and clinical care focuses on alleviating symptoms by providing respiratory and cardiac support (Straub and Bushby, 2008).…”

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

“…SGCG mutations commonly disrupt the reading frame and result in the absence of γ-sarcoglycan protein expression (3,8,9). There are currently no approved therapies for treating LGMD 2C, and the mainstay of medical treatment relies on supportive care (10).…”